The overall objective of this research plan is to uncover the physiological functions of IL-24, a new cytokine that we recently discovered. IL-24 belongs to the IL-10 family of cytokines that signal through highly related heterodimeric type II cytokine receptors. The relevance of IL-24 signaling to epidermal functions is based on the following evidence. First, epidermis (specifically keratinocytes) is one of the major target tissues of IL-24 based on the expression pattern of the two IL-24 receptors that we identified. Secondly, activated T lymphocytes, in particular the TH2 cells, are the major source of IL-24 production, and these cells are known to reside within epidermis (especially during wound healing) and psoriatic lesions. Accordingly, we hypothesize that IL-24 may be an important regulator for at least two epidermal functions. First, IL-24 may function, in an analogous manner to IL-10 on hematopoietic cells, to inhibit the syntheses of proinflammatory cytokines such as IL-1 and TNF-alpha by epidermis. In this regard, IL-24, like IL-10, may function as a major anti-inflammatory cytokine that signals the attenuation or ultimate termination of inflammatory responses in the skin during the wound healing process. This is supported by the tissue specific nature of receptor expression for IL-10 in hematopoietic cells and for IL-24 in non-hematopoietic origins such as epidermis. Secondly, IL-24 may function as a signal for keratinocyte proliferation, migration and differentiation during tissue repair. We propose the following specific aims to test our hypothesis: Specific Aim 1: To determine the biological functions of IL-24 on keratinocytes - 1a: To determine if IL-24 can inhibit the production of proinflammatory cytokines by keratinocytes in response to bacterial lipopolysaccharide (LPS) - 1b: To determine if IL-24 can promote keratinocyte proliferation and migration - Specific Aim 2: To determine the expression pattern of IL-24 and its receptors during tissue repair and psoriasis - 2a: Cellular localizations of IL-24 and IL-24 receptor expression in cutaneous excisional wounds - 2b: Comparison of the expression level of IL-24 and IL-24 receptors between normal and psoriatic skins